tbuckley/cabot-search huggingface dataset:
Actively replicating gut bacteria identified by 5-ethynyl-2’-deoxyuridine (EdU) click chemistry and cell sorting
Authors: Eve T. Beauchemin, Claire Hunter, Corinne F. Maurice
Journal: Gut Microbes (2023)

The composition of the intestinal bacterial community is well described, but recent research suggests that the metabolism of these bacteria plays a larger role in health than which species are present. One fundamental aspect of gut bacterial metabolism that remains understudied is bacterial replication. Indeed, there exist few techniques which can identify actively replicating gut bacteria. In this study, we aimed to address this gap by adapting 5-ethynyl-2'-deoxyuridine (EdU) click chemistry (EdU-click), a metabolic labeling method, coupled with fluorescence-activated cell sorting and sequencing (FACS-Seq) to characterize replicating gut bacteria. We first used EdU-click with human gut bacterial isolates and show that many of them are amenable to this technique. We then optimized EdU-click and FACS-Seq for murine fecal bacteria and reveal that Prevotella UCG-001 and Ileibacterium are enriched in the replicating fraction. Finally, we labeled the actively replicating murine gut bacteria during exposure to cell wall-specific antibiotics in vitro. We show that regardless of the antibiotic used, the actively replicating bacteria largely consist of Ileibacterium, suggesting the resistance of this taxon to perturbations. Overall, we demonstrate how combining EdU-click and FACSeq can identify the actively replicating gut bacteria and their link with the composition of the whole community in both homeostatic and perturbed conditions. This technique will be instrumental in elucidating in situ bacterial replication dynamics in a variety of other ecological states, including colonization and species invasion, as well as for investigating the relationship between the replication and abundance of bacteria in complex communities.
Intestinal group 1 innate lymphoid cells drive macrophage-induced inflammation and endocrine defects in obesity and promote insulinemia
Authors: Rebeca Liébana-García, Marta Olivares, Carlos Francés-Cuesta, Teresa Rubio, Valerio Rossini, Guillermo Quintas, Yolanda Sanz
Journal: Gut Microbes (2023)

Hypercaloric diets overactivate the intestinal immune system and disrupt the microbiome and epithelial cell functions, impairing glucose metabolism. The origins of this inflammatory cascade are poorly characterized. We investigated the involvement of intestinal proinflammatory group 1 innate lymphoid cells (ILC1s) in obesity progression and metabolic disruption. In obese mice, we studied longitudinally the ILC1s response to the diet and ILC1s depletion to address its role in obesity. ILC1s are required for the expansion of pro-inflammatory macrophages and ILC2s. ILC1s depletion induced the ILC3-IL-22 pathway, increasing mucin production, antimicrobial peptides, and neuroendocrine cells. These changes were translated into higher gut hormones and reduced insulinemia and adiposity. ILC1s depletion was also associated with a bloom in Akkermansia muciniphila and decreases in Bilophila spp. Intestinal-ILC1s are upstream activators of inflammatory signals, connecting immunity with the microbiome, the enteroendocrine system, and the intestinal barrier in the control of glucose metabolism and adiposity.
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Journal: JAMA Network Open (2023)

Kevin W. Garey, PharmD, MS; Jinhee Jo, PharmD; Anne J. Gonzales-Luna, PharmD; Brittany Lapin, PhD; Abhishek Deshpande, MD, PhD; Elaine Wang, MD; Brooke Hasson, PhD; Sissi V. Pham, PharmD; Shirley P. Huang, PharmD, MS; Pat Ray Reese, PhD; Henry Wu, PhD; Elizabeth Hohmann, MD; Paul Feuerstadt, MD; Caterina Oneto, MD; Charles S. Berenson, MD; Christine Lee, MD; Barbara McGovern, MD; Lisa vonMoltke, MD
Radiosensitization of IDH-Mutated Gliomas through ZMYND8 – a Pathway to Improved Outcomes
Authors: Sean Sachdev, Crismita Dmello, Adam M. Sonabend
Journal: Clinical Cancer Research (2023)

Summary Isocitrate dehydrogenase 1–mutant (IDH1m) gliomas are recalcitrant tumors for which radiotherapy remains a standard treatment. A recent study identified ZMYND8 as a key mediator of radioresistance for IDH1m gliomas, and pharmacologic targeting of this pathway may heighten radiotherapy-induced tumor response, providing a prospect of improved clinical outcomes. See related article by Carney et al., p. 1763
US Medical School Admissions Leaders’ Experiences With Barriers to and Advancements in Diversity, Equity, and Inclusion
Authors: Michelle Ko, Mark C. Henderson, Tonya L. Fancher, Maya R. London, Mark Simon, Rachel R. Hardeman
Journal: JAMA Network Open (2023)

Importance Despite decades-long calls for increasing racial and ethnic diversity, the medical profession continues to exclude members of Black or African American, Hispanic or Latinx, and Indigenous groups. Objective To describe US medical school admissions leaders’ experiences with barriers to and advances in diversity, equity, and inclusion. Design, Setting, and Participants This qualitative study involved key-informant interviews of 39 deans and directors of admission from 37 US allopathic medical schools across the range of student body racial and ethnic composition. Interviews were conducted in person and online from October 16, 2019, to March 27, 2020, and analyzed from October 2019 to March 2021. Main Outcomes and Measures Participant experiences with barriers to and advances in diversity, equity, and inclusion. Results Among 39 participants from 37 medical schools, admissions experience ranged from 1 to 40 years. Overall, 56.4% of participants identified as women, 10.3% as Asian American, 25.6% as Black or African American, 5.1% as Hispanic or Latinx, and 61.5% as White (participants could report &amp;amp;gt;1 race and/or ethnicity). Participants characterized diversity broadly, with limited attention to racial injustice. Barriers to advancing racial and ethnic diversity included lack of leadership commitment; pressure from faculty and administrators to overemphasize academic scores and school rankings; and political and social influences, such as donors and alumni. Accreditation requirements, holistic review initiatives, and local policy motivated reforms but may also have inadvertently lowered expectations and accountability. Strategies to overcome challenges included narrative change and revision of school leadership structure, admissions goals, practices, and committee membership. Conclusions and Relevance In this qualitative study, admissions leaders characterized the ways in which entrenched beliefs, practices, and power structures in medical schools may perpetuate institutional racism, with far-reaching implications for health equity. Participants offered insights on how to remove inequitable structures and implement process changes. Without such action, calls for racial justice will likely remain performative, and racism across health care institutions will continue.
Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility
Authors: Lauren M. Hurwitz, Penelope M. Webb, Susan J. Jordan, Jennifer A. Doherty, Holly R. Harris, Marc T. Goodman, Yurii B. Shvetsov, Francesmary Modugno, Kirsten B. Moysich, Joellen M. Schildkraut, Andrew Berchuck, Hoda Anton-Culver, Argyrios Ziogas, Usha Menon, Susan J. Ramus, Anna H. Wu, Celeste Leigh Pearce, Nicolas Wentzensen, Shelley S. Tworoger, Paul D. P. Pharoah, Britton Trabert
Journal: JAMA Network Open (2023)

Importance Frequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups. Objective To evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer. Design, Setting, and Participants We pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022. Exposures Frequent aspirin use, defined as daily or almost daily use for 6 months or longer. Main Outcomes and Measures The main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS. Results There were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype. Conclusions and Relevance The findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.
Understanding and Addressing How Racism Can Affect Medical School Admissions—Making the Invisible Visible
Authors: Camila M. Mateo, David R. Williams
Journal: JAMA Network Open (2023)

Michelle Ko, MD, PhD; Mark C. Henderson, MD; Tonya L. Fancher, MD, MPH; Maya R. London, BA; Mark Simon, MA; Rachel R. Hardeman, PhD, MPH
Outcomes of Chemoimmunotherapy Among Patients With Extensive-Stage Small Cell Lung Cancer According to Potential Clinical Trial Eligibility
Authors: Daichi Fujimoto, Takeshi Morimoto, Motohiro Tamiya, Akito Hata, Hirotaka Matsumoto, Atsushi Nakamura, Toshihide Yokoyama, Yoshihiko Taniguchi, Junji Uchida, Yuki Sato, Takashi Yokoi, Hisashi Tanaka, Naoki Furuya, Takeshi Masuda, Yoshihiko Sakata, Eisaku Miyauchi, Satoshi Hara, Go Saito, Satoru Miura, Masaki Kanazu, Nobuyuki Yamamoto, Hiroaki Akamatsu
Journal: JAMA Network Open (2023)

Chemoimmunotherapy is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). However, whether findings from pivotal trials can be extrapolated to the clinical practice setting remains unclear.To compare treatment outcome gaps following first-line chemoimmunotherapy for patients with ES-SCLC between those who met and did not meet the eligibility criteria used in previous clinical trials.A prospective cohort study was conducted from September 1, 2019, to September 30, 2020, at 32 hospitals in Japan, with at least 12 months of follow-up. Participants included consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as first-line therapy.Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered trial-eligible.The primary outcome was 6-month progression-free survival. The secondary outcomes were differences in progression-free survival, overall survival, and safety according to whether key clinical trial eligibility criteria were met.A total of 207 patients were analyzed (median age, 72 years; range, 46-87 years; 170 [82%] were male). Sixty-four patients (31%) were older adults (age ≥75 years), and most (184 [89%]) had an Eastern Cooperative Oncology Group performance status of 0 or 1. There were 132 (64%) trial-eligible patients. The 6-month progression-free survival rate for all patients was 38.8% (95% CI, 32.4%-45.7%). The median progression-free survival was 5.1 months in trial-eligible patients and 4.7 months in trial-ineligible patients (hazard ratio, 0.72; 95% CI, 0.53-0.97; P = .03). The proportion of patients who achieved disease control was 93% (118 of 127) in trial-eligible patients and 77% (55 of 71) in trial-ineligible patients (P = .002). The median overall survival was 15.8 months in trial-eligible patients and 13.1 months in trial-ineligible patients (hazard ratio, 0.73; 95% CI, 0.51-1.07; P = .10). The rate of severe adverse events was numerically higher among trial-ineligible patients than among trial-eligible patients (39% vs 27%; P = .07).In this cohort study, the overall treatment outcome was comparable to that reported in pivotal clinical trials. However, treatment outcomes after chemoimmunotherapy might differ between trial-eligible and trial-ineligible patients. These findings suggest that trial-eligibility criteria may be useful in clinical practice, and further studies using data from clinical practice settings are required to inform regulatory approval and clinical decision-making.
Preserving Pancreatic Beta Cell Function in Recent-Onset Type 1 Diabetes
Authors: Jennifer Couper
Journal: JAMA (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Assessment of Alcohol Exposure From Alcohol-Based Disinfectants Among Premature Infants in Neonatal Incubators in Japan
Authors: Daisuke Hitaka, Satoshi Fujiyama, Yukiko Nishihama, Ryota Ishii, Yusuke Hoshino, Hiromi Hamada, Yayoi Miyazono, Shoji F. Nakayama, Hidetoshi Takada
Journal: JAMA Network Open (2023)

Importance The risk of premature infants in neonatal incubators exposed to evaporated alcohol from alcohol-based disinfectants (ABDs) is unknown. Objective To assess alcohol concentrations in the peripheral blood of premature infants and neonatal incubators. Design, Setting, and Participants A quality improvement study comparing 2 different populations before and after introduction of ABD practice (ABD-PRAC) was conducted in a neonatal intensive care unit of a single tertiary hospital in Japan. Participants included premature infants who were born before 34 weeks of gestational age and received medical care in neonatal incubators. The study consisted of 3 periods: (1) September 1, 2020, to August 1, 2021 (prospective observation of pre–ABD-PRAC, (2) August 2 to August 22, 2021 (introduction of ABD-PRAC to medical staff and parents in the neonatal intensive care unit), and (3) August 23, 2021, to March 31, 2022 (prospective observation of post–ABD-PRAC). No follow-up studies were initiated. Interventions An ABD-PRAC that aimed to reduce alcohol evaporation from ABDs inside neonatal incubators was instituted: (1) place alcohol preps in the incubator just before use and remove them from the incubator as soon as possible and (2) withhold placing hands into the incubators until 60 seconds after using ABDs for disinfection (applied only to family members). Main Outcomes and Measures Blood alcohol concentration and evaporated alcohol concentrations in neonatal incubators. Results Disinfectant practice was assessed among 28 infants during the pre–ABD-PRAC (17 infants [10 girls]; median gestational age at birth, 29.4 [IQR, 26.3-30.3] weeks) and post–ABD-PRAC (11 infants [3 girls]; median gestational age at birth, 30.0 [IQR, 25.3-32.2] weeks) study periods. The median blood alcohol concentration was 7.0 (IQR, 5.4-9.3) mg/dL pre–ABD-PRAC and 4.2 (IQR, 2.5-7.2) mg/dL post–ABD-PRAC. The median evaporated alcohol concentration inside neonatal incubators during pre–ABD-PRAC during the day was 23.6 (IQR, 15.9-36.5) ppm and, at night, was 13.2 (IQR, 8.9-19.4) ppm; during post–ABD-PRAC, the concentration was 9.4 (IQR, 6.0-16.0) ppm during the day and 5.7 (IQR, 3.6-9.7) ppm at night. The introduction of ABD-PRAC at 22 weeks’ corrected gestational age was associated with a lower blood alcohol concentration in premature infants: regression coefficient value, −8.3 (95% CI, −12.0 to −4.7). Conclusions and Relevance In this study, alcohol evaporated from ABDs was absorbed by premature infants in neonatal incubators. The findings suggest that introduction of ABD-PRAC was associated with lower alcohol concentrations in neonatal incubators and in the blood of premature infants.
Association of Long-term Exposure to Particulate Air Pollution With Cardiovascular Events in California
Authors: Stacey E. Alexeeff, Kamala Deosaransingh, Stephen Van Den Eeden, Joel Schwartz, Noelle S. Liao, Stephen Sidney
Journal: JAMA Network Open (2023)

Long-term exposure to fine particulate air pollution (PM2.5) is a known risk factor for cardiovascular events, but controversy remains as to whether the current National Ambient Air Quality Standard (12 μg/m3 for 1-year mean PM2.5) is sufficiently protective.
Precision Hydrogels for the Study of Cancer Cell Mechanobiology
Authors: Jana Sievers, Vaibhav Mahajan, Petra B. Welzel, Carsten Werner, Anna Taubenberger
Journal: Advanced Healthcare Materials (2023)

Abstract Cancer progression is associated with extensive remodeling of the tumor microenvironment (TME), resulting in alterations of biochemical and biophysical cues that affect both cancer and stromal cells. In particular, the mechanical characteristics of the TME extracellular matrix undergo significant changes. Bioengineered polymer hydrogels can be instrumental to systematically explore how mechanically changed microenvironments impact cancer cell behavior, including proliferation, survival, drug resistance, and invasion. This article reviews studies that have explored the impact of different mechanical cues of the cells’ 3D microenvironment on cancer cell behavior using hydrogel‐based in vitro models. In particular, advanced engineering strategies are highlighted for tailored hydrogel matrices recapitulating the TME's micrometer‐ and sub‐micrometer‐scale architectural and mechanical features, while accounting for its intrinsically heterogenic and dynamic nature. It is anticipated that such precision hydrogel systems will further the understanding of cancer mechanobiology.
Global Diabetes Prevalence in COVID-19 Patients and Contribution to COVID-19– Related Severity and Mortality: A Systematic Review and Meta-analysis
Authors: Rui Li, Mingwang Shen, Qianqian Yang, Christopher K. Fairley, Zhonglin Chai, Robert McIntyre, Jason J. Ong, Hanting Liu, Pengyi Lu, Wenyi Hu, Zhuoru Zou, Zengbin Li, Shihao He, Guihua Zhuang, Lei Zhang
Journal: Diabetes Care (2023)

COVID-19 and diabetes both contribute to large global disease burdens.
Tumor‐derived insulin‐like growth factor‐binding protein‐1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors
Authors: Hiroyuki Suzuki, Hideki Iwamoto, Takahiro Seki, Toru Nakamura, Atsutaka Masuda, Takahiko Sakaue, Toshimitsu Tanaka, Yasuko Imamura, Takashi Niizeki, Masahito Nakano, Shigeo Shimose, Tomotake Shirono, Yu Noda, Naoki Kamachi, Miwa Sakai, Kazutoyo Morita, Masamichi Nakayama, Tomoharu Yoshizumi, Ryoko Kuromatsu, Hirohisa Yano, Yihai Cao, Hironori Koga, Takuji Torimura
Journal: Cancer Communications (2023)

Abstract Background Antiangiogenic tyrosine kinase inhibitors (TKIs) provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma (HCC). However, patients with HCC often develop resistance toward antiangiogenic TKIs, and the underlying mechanisms are not understood. The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC. Methods We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients. We evaluated the prognosis, therapeutic response, and serum insulin‐like growth factor‐binding protein‐1 (IGFBP‐1) levels of 31 lenvatinib‐treated HCC patients. Based on the array of results, a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted. Additionally, in vivo genetic and pharmacological gain‐ and loss‐of‐function experiments were performed. Results In the patient cohort, IGFBP‐1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival. Mechanistically, antiangiogenic TKI treatment markedly elevated tumor IGFBP‐1 levels via the hypoxia‐hypoxia inducible factor signaling. IGFBP‐1 stimulated angiogenesis through activation of the integrin α5β1‐focal adhesion kinase pathway. Consequently, loss of IGFBP‐1 and integrin α5β1 by genetic and pharmacological approaches re‐sensitized HCC to lenvatinib treatment. Conclusions Together, our data shed light on mechanisms underlying acquired resistance of HCC to antiangiogenic TKIs. Antiangiogenic TKIs induced an increase of tumor IGFBP‐1, which promoted angiogenesis through activating the IGFBP‐1‐integrin α5β1 pathway. These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP‐1 inhibitors.
Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy
Authors: Yuanzhuo Gu, Zhengkui Zhang, Peter ten Dijke
Journal: Cellular and Molecular Immunology (2023)

Abstract Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, most patients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-to-mesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistance in cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsic mechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulate tumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects to enhance the ICB response for therapeutic gain in cancer patients.